Alzheimer’s diseases are characterized by an age-related buildup of toxic proteins in the brain. Advantx‘s candidates ADV462 and ADV368 have been designed to bind Sigma receptors and activate the displacement of toxic protein oligomers on neurons and allow the damage response mechanisms to return the cell to normal function.
Understanding Alzheimer’s Disease
In a healthy adult brain, there are about 100 billion neurons, each forming connections with other neurons through long, branching extensions. Alzheimer’s disease (AD) is defined neuropathologically by two neuronal lesions: intracellular protein tau aggregates of an abnormal form of the microtubule-associated called tau or neurofibrillary tangles and neuritic plaques composed of focally swollen (dystrophic) neurites (DNs), extracellular β-amyloid and many other proteins in clusters called beta-amyloid plaques. Additionally, in yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) containing incompletely digested autophagy substrates accumulate progressively packed into large membrane blebs forming flower-like perikaryal rosettes within affected neurons at the earliest disease stage and promoting senile amyloid plaques. The presence of plaques and tangles of these toxic proteins leads to thermogenic dysfunction, progressive failure of autophagy response, neuronal cell death involving lysosomal membrane permeabilization, mitochondrial degradation, cathepsin release, and, ultimately, glial invasion and extracellular plaque expansion, activation of the immune system, resulting in chronic inflammation and atrophy due to cell loss. Brain function is further compromised in Alzheimer’s disease by the brain’s decreased ability to metabolize glucose, its primary fuel, and the dysregulation of the excitatory glutamatergic transmission and synaptic failure.
Sigma receptors are considered one of the most interesting therapeutic targets for Alzheimer’s disease due to their multiple roles. They not only inhibit the deposition of beta-amyloid proteins and plaques in neurons, but also enhance the clearance of β-amyloid, a critical factor in the progression of Alzheimer’s disease. This promising strategy, combined with Sigma receptors’ role in inducing autophagy and proteostasis, and restoring synaptic connections, cholesterol synthesis and transport, and cellular homeostasis, positions them at the forefront of Alzheimer’s disease research.
Potential market for Advantx candidates in Alzheimer's disease
Prevalence>23m people in US/EU/UK/JP
Treated Population>10m patients in US/EU/UK/JP
Market Growthest. 18.5% CAGR
data from Globaldata
Differentiated stages of Alzheimer's disease
People with Early Alzheimer’s disease have subtle problems with memory and thinking, but these do not interfere with the ability to carry out daily activities. Among these people with mild cognitive impairment, about 15% develop dementia within two years, and about one-third (32%) within five years. Amyloid-β (Aβ) plaques start to accumulate ~20 years before symptom onset followed by the accumulation and spreading of neurofibrillary tau aggregates with ensuing neurodegeneration and AD dementia.
The disease initiates intracellularly, with deficiencies of lysosomal activity, mitochondrial impairment, autophagy dysfunction, tau hyperphosphorylation, formation of neurofibrillary tangles, and accumulation of APP-βCTF and Aβ selectively within poorly acidified AL, well before extracellular β-amyloid deposition.
ADV462 EAD is Advantx’s candidate for the treatment of early Alzheimer’s disease.
Late-onset Alzheimer’s disease comprises two distinct stages, moderate and severe. In the moderate stage, which is usually the longest, individuals may have difficulty communicating and performing routine tasks, and begin to have personality and behavioral changes. In the severe stage, individuals need help with activities of daily living and the effects of Alzheimer’s dementia on the physical health of individuals become especially evident destroying not only the patients’ quality of life but also its duration.
In the late stage of the disease, extracellular formation and expansion of senile plaques, glial invasion, neuroinflammation, and thermogenesis, result in synapses and neuronal loss, and many brain regions begin to shrink. By the final stages of Alzheimer’s, this process—called brain atrophy—is widespread, causing significant loss of brain volume.
ADV368 LAD is Advantx’s candidate for the treatment of late-onset Alzheimer’s disease.